WO2021121294A1 - Dérivé de triazolopyridazine, son procédé de préparation, composition pharmaceutique associée et utilisation correspondante - Google Patents

Dérivé de triazolopyridazine, son procédé de préparation, composition pharmaceutique associée et utilisation correspondante Download PDF

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WO2021121294A1
WO2021121294A1 PCT/CN2020/136998 CN2020136998W WO2021121294A1 WO 2021121294 A1 WO2021121294 A1 WO 2021121294A1 CN 2020136998 W CN2020136998 W CN 2020136998W WO 2021121294 A1 WO2021121294 A1 WO 2021121294A1
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alkyl
group
membered
methyl
cycloalkyl
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PCT/CN2020/136998
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English (en)
Chinese (zh)
Inventor
金赟
王非
吴金华
陈南阳
孙勇
李帅
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上海赛默罗生物科技有限公司
上海赛默罗德生物科技有限公司
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Priority to BR112022011946A priority Critical patent/BR112022011946A2/pt
Application filed by 上海赛默罗生物科技有限公司, 上海赛默罗德生物科技有限公司 filed Critical 上海赛默罗生物科技有限公司
Priority to PE2022001105A priority patent/PE20221517A1/es
Priority to AU2020410470A priority patent/AU2020410470B2/en
Priority to CN202080061283.4A priority patent/CN114302886B/zh
Priority to JP2022537266A priority patent/JP7417742B2/ja
Priority to US17/786,528 priority patent/US20230136194A1/en
Priority to IL293959A priority patent/IL293959A/en
Priority to CA3161739A priority patent/CA3161739A1/fr
Priority to MX2022007426A priority patent/MX2022007426A/es
Priority to EP20904065.8A priority patent/EP4079734A4/fr
Priority to KR1020227024733A priority patent/KR20220140710A/ko
Publication of WO2021121294A1 publication Critical patent/WO2021121294A1/fr
Priority to CONC2022/0009489A priority patent/CO2022009489A2/es

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    • C07—ORGANIC CHEMISTRY
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to triazolopyridazine derivatives with modulating function for ⁇ 5-GABA A receptors, their preparation, pharmaceutical compositions containing them, and their use as medicines.
  • GABA Gamma-aminobutyric acid
  • GABA A receptors which are ligands.
  • GABA B receptor which is a member of the G protein-coupled receptor superfamily.
  • the GABA A receptor subunits in mammals are found to be ⁇ 1-6, ⁇ 1-4, ⁇ 1-3, ⁇ , ⁇ , ⁇ , and ⁇ 1-2, among which ⁇ subunits, ⁇ subunits and ⁇ subunits
  • the base pair is essential to form a complete functional GABA A receptor, and the ⁇ subunit is essential for the binding of benzodiazepine to the GABA A receptor.
  • GABA A receptors containing ⁇ 5 account for less than 5% of GABA A receptors in the mammalian brain, and the expression level is very low in the cerebral cortex, but GABA in the hippocampus of the brain The proportion of A receptors is greater than 20%, and other brain regions are hardly expressed.
  • ⁇ 5-GABA A receptors account for less than 5% of GABA A receptors in the mammalian brain, and the expression level is very low in the cerebral cortex, but GABA in the hippocampus of the brain The proportion of A receptors is greater than 20%, and other brain regions are hardly expressed.
  • many pharmaceutical companies including Roche are engaged in the research of ⁇ 5-GABA A receptor ligands, and a large number of compounds have been synthesized one after another.
  • inverse agonists of GABA A receptors containing ⁇ 5 subunits in the hippocampus of the brain among which ⁇ 5IA and MRK-016 have shown good effects in treating cognitive diseases in animal disease models. It is generally believed that inverse agonists of the GABA A receptor of the ⁇ 5 subunit can be used to treat cognitive diseases, especially Alzheimer's disease.
  • Patent application US 2011 0224278 A1 discloses that inverse agonists of GABA A receptors containing ⁇ 5 subunits can be used to treat multi-infarct dementia and stroke-related diseases.
  • ⁇ 5-GABA a receptor inverse agonists by selective binding to a receptor ⁇ 5-GABA a peripheral nervous system, the effect of suppressing action of various types of pain, animal model data, inverse agonist
  • the invention provides a triazolopyridazine derivative, its preparation method, pharmaceutical composition and application.
  • Such compounds have good inverse agonistic activity, thermodynamic solubility, bioavailability and pharmacokinetic properties for ⁇ 5-GABA A.
  • the present invention provides a compound as shown in formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, its hydrate , Its pharmaceutically acceptable salt or its prodrug,
  • Z is a 5-membered or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, the heteroaromatic ring is optionally substituted by one or more R 3;
  • R 3 is independently halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy (C 1-6 ) alkyl, C 3-6 cycloalkyl (C 1-6 ) alkoxy, C 3-6 cycloalkyl (C 1-6 ) alkoxy (C 1-6 ) alkyl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkyl (C 1-6 ) alkyl , Which may each be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkylamino;
  • R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-7 heterocycloalkyl, C 3-6 cycloalkyl (C 1-6 ) alkyl or C 1-6 alkane
  • An oxy (C 1-6 ) alkyl group each of which may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 alkyl, C 1- 6 alkoxy and C 1-6 alkylamino;
  • R 2 is a heterocyclic group, a phenyl group or a heteroaryl group, each of which may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C (O) R, -NHR, C 3-6 alkenyl, cycloalkyl, -NR 4 R 5, -C ( O) NR 4 R 5, -COOH, -SO 2 -C 1- 6 alkyl and -SO 2 NR 6 R 7 ;
  • R is independently H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, heterocyclyl, aryl or heteroaryl, which may each be Optionally substituted by 1-3 R';
  • R' -1 is independently C 1-6 alkyl
  • R 8 and R 9 are independently H or C 1-6 alkyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group, and the heteroatom is selected from one of N, S and O One or more species, the number is 1, 2 or 3;
  • R'-2 is C 3-6 cycloalkyl or C 1-6 alkyl
  • R'-3 is independently C 1-6 alkyl
  • R 10 is C 1-6 alkyl
  • R 4 and R 5 are independently H, C 1-6 alkyl or C 3-6 cycloalkyl, or R 4 and R 5 together with the nitrogen atom to which they are connected form a 5- or 6-membered heterocycloalkyl group, heteroatom
  • N, S and O the number is 1, 2 or 3; each can be optionally substituted by 1 to 5 substituents, and the substituents are independently selected from: amino, halogen , Hydroxy, C 1-6 alkyl and C 1-6 alkoxy;
  • R 6 and R 7 are independently C 1-6 alkyl.
  • the compound I in its pharmaceutically acceptable salts or prodrugs, the definitions of certain groups can be as follows (unannotated definitions are the same as those described above, hereinafter referred to as in a technical solution):
  • X is N or CH
  • the formula II is as shown in formula III, IV or V:
  • Y is C or N;
  • A is 5-6 membered heterocyclic ring, 5-6 membered heteroaromatic ring or not present, and the heteroatoms in said 5-6 membered heterocyclic ring and 5-6 membered heteroaromatic ring are independent
  • the ground is N, the number is 1 or 2; n is any integer of 0-4.
  • the Z when the Z is a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, said Z contains 1, 2 or 3 independent heteroatoms.
  • the 5-membered heteroaromatic ring of heteroatoms selected from oxygen, nitrogen and sulfur is, for example, a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, or isoxazole, for example, More for example
  • the b end is connected to the R 3 described above.
  • the R 3 is, for example, the same or different.
  • the number of R 3 is, for example, one or two.
  • said R 3 is C 1-6 alkyl
  • said C 1-6 alkyl is, for example C 1-3 alkyl, or for example, methyl, ethyl, n Propyl or isopropyl is also, for example, methyl.
  • the alkyl end can be connected to the Z.
  • said R 3 is C 1-6 alkoxy C 1-6 alkyl
  • said C 1-6 alkoxy is, for example, C 1-4 alkoxy (such as Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy)
  • another example is C 1-3 alkoxy ( Such as methoxy, ethoxy, n-propoxy or isopropoxy), also for example methoxy.
  • said C 1-6 alkyl is, for example C 1-4 alkyl (methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example C 1-3 alkyl (methyl, ethyl, n-propyl or isopropyl Group), also for example methyl.
  • the C 1-6 alkoxy C 1-6 alkyl is, for example, C 1- alkoxy C 1-3 alkyl, and for example,
  • the number of the substituents is, for example, 1, 2, 3, or 4, and for example, 1 Or 2.
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and for example For methyl.
  • C 1-4 alkyl e.g. methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl
  • said R 3 is a hydroxy-substituted C 1-6 alkyl group
  • said R 3 is, for example
  • said C 1-6 alkyl is, for example C 1-4 alkyl, or for example, methyl, ethyl, n Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the halogen is, for example, fluorine, chlorine, bromine, or iodine, or for example, fluorine.
  • the number of the substituents is, for example, 1, 2, 3, or 4, and for example, 1 Or 2.
  • the R 1 is a C 1-6 alkyl group, and the C 1-6 alkyl group is substituted by 1-4 substituents, the R 1 is, for example, 2
  • the halogen-substituted methyl is another example of difluoromethyl.
  • the R 1 is a C 3-6 cycloalkyl (C 1-6 ) alkyl group
  • the C 1-6 alkyl group is, for example, a C 1-4 alkyl group, and For example, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also for example methyl.
  • the R 1 is a C 3-6 cycloalkyl (C 1-6 ) alkyl group
  • the C 3-6 cycloalkyl group is, for example, cyclopropyl or cyclobutyl.
  • Cyclopentyl or cyclohexyl another example is cyclopropyl or cyclobutyl.
  • the R 1 is a C 3-6 cycloalkyl (C 1-6 ) alkyl group
  • the C 3-6 cycloalkyl (C 1-6 ) alkyl group is for example Is a C 3 cycloalkyl (C 1-3 ) alkyl group
  • another example is
  • the chiral carbon atom is, for example, in the R configuration Carbon atom or S configuration carbon atom.
  • the heteroaryl group is, for example, a 5-10 membered heteroaryl group, the heteroatom is nitrogen and/or oxygen, and the number is 1-4 ;
  • Another example is 5-6 membered monocyclic heteroaryl or 9-10 membered bicyclic heteroaryl (the 9-10 membered bicyclic heteroaryl group such as 5-6 membered heteroaryl and 5-6 membered heteroaryl Bicyclic heteroaryl, or, 5-6 membered heteroaryl and 5-6 membered heterocyclic bicyclic heteroaryl), for example triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , Pyrazolopyridyl, pyrrolopyridinyl, pyridopyrrolidinyl, naphthyridinyl, quinolinyl, imidazopyridinyl, dioxalinopyridinyl, dioxalinopyridinyl
  • Another example is
  • R 2 is a 9-10 membered bicyclic heteroaryl formed by a 5-6 membered heteroaryl group and a 5-6 membered heterocyclic group
  • the substitution position of the said substituent is located at the On the heteroatom in the 5-6 membered heterocyclic group mentioned above.
  • the number of the substituents is, for example, 1, 2, 3, or 4, and for example, 1 Or 2.
  • the halogen is, for example, fluorine, chlorine, bromine or iodine, or for example, fluorine or chlorine.
  • the C 3-6 alkenyl cycloalkyl group is, for example, cyclopropenyl, cyclobutenyl, or cyclopropenyl. Pentenyl or cyclohexenyl, another example is
  • the C 1-6 alkyl is, for example, C 1-4 alkyl (such as methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl Group), also for example methyl and ethyl.
  • C 1-4 alkyl such as methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl Group
  • said R is independently C 1-6 alkyl
  • said C 1-6 alkyl is, for example C 1-4 alkyl, or for example, methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl, isopropyl or tert-butyl.
  • the R is independently C 1-6 alkenyl
  • the C 1-6 alkenyl is, for example, C 2-3 alkenyl, or ethylene
  • the C 3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl , For example, cyclobutyl or cyclopropyl.
  • the heterocyclic group is, for example, a 3-10 membered heterocyclic group
  • the heteroatom is nitrogen and/or oxygen
  • the number is 1 or 2 or 3, for example a 5-6 membered monoheterocyclic group or a 7-8 membered heterospirocyclic group
  • the heteroatom is nitrogen and/or oxygen
  • the number is 1 or 2
  • the number is for example morpholinyl, Pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyran, tetrahydrofuran or 2-oxo-[3,3]heptanyl, for example
  • Another example is
  • the R is a C 3-6 cycloalkenyl group
  • the C 3-6 cycloalkenyl group is, for example, cyclohexene, cyclopropyl or cyclobutyl, for example,
  • the aryl group is, for example, a C 6-14 aryl group, another example is a phenyl group, a naphthyl group, a phenanthryl group, or an anthryl group, and another example is a benzene group. base.
  • the heteroaryl group is, for example, a 5-10 membered heteroaryl group
  • the heteroatom is nitrogen and/or oxygen
  • the number is 1, 2 or 3, for example a 5-membered monocyclic heteroaryl group
  • the heteroatom is nitrogen and/or oxygen
  • the number is 2 or 3, such as pyrimidinyl, oxadiazolyl or isoxazole, for example
  • the halogen is, for example, fluorine, chlorine, bromine or iodine, or for example, fluorine.
  • the R' is C 3-6 cycloalkyl
  • the C 3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, For example, it is cyclopropyl.
  • said R' is independently C 1-6 alkylamino
  • said C 1-6 alkylamino is, for example, C 1-3 alkylamino, or for example, ethyl
  • the amino group is also, for example, -NHEt.
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl, n Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example C 1-3 alkyl (methyl, ethyl, n-propyl or isopropyl), and For example, methyl.
  • C 1-4 alkyl e.g. methyl, ethyl, n Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl methyl, ethyl, n-propyl or isopropyl
  • the C 1-6 alkoxy is, for example, C 1-4 alkoxy (methoxy, ethyl group, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy), and for example, C 1- 3 alkoxy group (methoxy, ethoxy, Oxy, n-propoxy or isopropoxy), also for example methoxy.
  • the R' is independently a cyano group or a halogen-substituted C 1-3 alkyl group
  • the C 1-3 alkyl group is, for example, methyl, ethyl, or n-propyl.
  • Group or isopropyl group for example also methyl group.
  • the R' is independently a cyano group or a halogen-substituted C 1-3 alkyl group
  • the R' is, for example,
  • the C 1-6 alkyl group of the C 1-6 alkyl group is, for example, a C 1-4 alkyl sulfone.
  • Group (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) another example is C 1-3 alkyl (methyl, ethyl, n-butyl) Propyl or isopropyl), also for example methyl.
  • the R' is independently C 1-6 alkyl sulfone
  • the C 1-6 alkyl sulfone is, for example, -SO 2 Me, -CH 2 CH 2 SO 2 Me
  • Another example is -SO 2 Me.
  • the heterocyclic group is, for example, a 3-6 membered monocyclic heterocyclic group, and the heteroatom is nitrogen and/or oxygen, and the number is One or two, for example tetrahydrofuranyl, oxetanyl, azetidinyl, morpholinyl or piperazinyl, and for example Another example is
  • the R' is a heteroaryl group
  • the heteroaryl group is, for example, a 5-10 membered heteroaryl group
  • the heteroatom is nitrogen and/or oxygen, and the number is 1, 2.
  • another example is a 5-membered monocyclic heteroaryl group
  • the heteroatom is nitrogen and/or oxygen, and the number is 2 or 3
  • another example is pyrimidinyl, oxadiazolyl or isoxazole
  • another example is
  • the heteroaryl group is, for example, a 5-6 membered heteroaryl group.
  • Aryl the heteroatom is nitrogen and/or oxygen, the number is 1, 2 or 3, such as oxadiazole or oxadiazole, and for example
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl, , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl ), also for example methyl.
  • C 1-4 alkyl e.g. methyl, ethyl, , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl
  • said R ' when said R 'is independently R' -1 substituted 5-10 membered heteroaryl, said R '-1 substituted 5-10 membered heteroaryl e.g. for
  • the R' is independently a C 3-6 cycloalkyl substituted with 1-3 cyano groups
  • the C 3-6 cycloalkyl is, for example, a 5-membered bicyclic bridge Cycloalkyl, for example
  • the R' is independently a C 6-14 aryl group
  • the C 6-14 aryl group is, for example, phenyl, naphthyl, phenanthryl or anthracenyl, for example Phenyl.
  • the R' is independently a 3-6 membered heterocyclic group substituted by 1-3 R'-3
  • the 3-6 membered heterocyclic group is, for example, 4-6 membered monoheterocyclic group
  • the heteroatom is nitrogen and/or oxygen
  • the number is 1 or 2
  • it is also piperazinyl or oxetanyl, and is also for example
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl, , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl ), also for example methyl.
  • C 1-4 alkyl e.g. methyl, ethyl, , N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl
  • R' is independently a 3-6 membered heterocyclic group substituted with 1-3 R'-3
  • said R'-3 is substituted with 1-3 R'-3.
  • the 3-6 membered heterocyclic group is for example
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl Group), also for example methyl.
  • C 1-4 alkyl e.g. methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl Group
  • the 5- or 6-membered heterocyclic group is, for example,
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and for example For methyl.
  • C 1-4 alkyl e.g. methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl
  • said C 1-6 alkyl is, for example C 1-4 alkyl, for example methyl and , Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or n-propyl.
  • the C 3-6 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl or cyclohexyl is also, for example, cyclohexyl.
  • the 5- or 6-membered heterocycloalkyl group is, for example,
  • the halogen is, for example, fluorine, chlorine, bromine or iodine, and For example, fluorine.
  • the number of the substituents is, for example, 1, 2, 3, 4 or 5 , For example, one or two or three.
  • said C 1-6 alkyl is, for example C 1-4 alkyl (e.g. methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and for example C 1-3 alkyl (such as methyl, ethyl, n-propyl or isopropyl Group), also for example methyl.
  • C 1-4 alkyl e.g. methyl, ethyl Group, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl or isopropyl Group
  • R 2 when R 2 is substituted by 1-4 substituents, and the substituent is -R, the -R is -C 1-6 alkyl, -C 1-6 alkenyl , -C 3-6 cycloalkyl, -heterocyclyl, -aryl or -heteroaryl.
  • R 2 when R 2 is substituted by 1-4 substituents, and the substituents are -OR, the -OR is -OC 1-6 alkyl or -O-heterocyclyl.
  • R 2 when R 2 is substituted by 1-4 substituents, and the substituent is -C(O)R, the -C(O)R is -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkenyl, -C(O)-C 3-6 cycloalkyl or -C(O)-aryl.
  • R 3 is independently C 1-6 alkyl or C 1-6 alkoxy (C 1-6 ) alkyl; R 3 is optionally substituted with 1-4 hydroxy groups.
  • R 3 is methyl
  • -Z is a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen and nitrogen.
  • R 1 is C 1-6 alkyl or C 3-6 cycloalkyl (C 1-6 ) alkyl, and R 1 is optionally substituted with 1-4 halogens.
  • R 1 is methyl, ethyl
  • R 2 is a phenyl group or a heteroaryl group; the heteroaryl group is a 5-10 membered heteroaryl group, the heteroatom is nitrogen and/or oxygen, and the number of heteroatoms is 1-4 ; Preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group.
  • R 2 is phenyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolidinyl, naphthyridine Group, quinolinyl, imidazopyridyl, dioxapyridyl, pyridooxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl , Pyridoimidazolyl, pyridotriazolyl, pyridonyl, pyridotriazolyl, pyridazinone, heteronaphthyl, naphthyridinone, imidazopyridazinyl, indolyl or n
  • they are pyridyl, pyridazinyl,
  • said R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -NHR, C 3 -6 alkenyl cycloalkyl, -NR 4 R 5 , -SO 2 -C 1-6 alkyl and -SO 2 NR 6 R 7 , preferably cyano, -R and -OR.
  • said R 2 is substituted by 1-4 substituents independently selected from the following groups: Me, -Et, -iPr, -CF 3 , -OCF 3 , -OCHF 2 , -Cl , -F, -CN, -OMe, -OEt, -NMe 2 , -CH 2 CF 3 , -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 NHEt, -OCHF 2 , -OCH (CH 3 ) 2 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 3 OCH 3 , -SO 2 Me, -CH 2 CH 2 SO 2 Me, -COOH,
  • R 3 is C 1-6 alkyl or C 1-6 alkoxy (C 1-6 ) alkyl, and R 3 is optionally substituted with 1-4 hydroxy groups;
  • R 1 is C 1-6 alkyl or C 3-6 cycloalkyl (C 1-6 ) alkyl, R 1 is optionally substituted with 1-4 halogens;
  • R 2 is phenyl or heteroaryl; R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O) R, C 3-6 alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl, and -SO 2 NR 6 R 7 ; Said -R is C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl or heteroaryl; said -OR is -OC 1-6 Alkyl or -O-heterocyclyl; said -C(O)R is -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkenyl, -C(O) ) -C 3-6 cycloalkyl or -
  • R 1 is methyl, ethyl
  • R 3 is methyl
  • R 2 is phenyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolopyridyl, pyrrolopyridyl, pyridopyrrolidinyl, naphthyridinyl, quinolinyl, imidazole Pyridyl, dioxalandopyridyl, pyridooxazinyl, pyrazolopyrimidinyl, pyridopyrazolyl, pyridopyrrolyl, pyridopyrazolyl, pyridonyl, pyridoimidazolyl, pyridine Tetrazolyl, pyridonyl, pyridotriazolyl, pyridazinonyl, phthalazinyl, naphthyridinyl, imidazopyridazinyl, indolyl or naphthalazin
  • R 3 is C 1-6 alkyl or C 1-6 alkoxy (C 1-6 ) alkyl, and R 3 is optionally substituted with 1-4 hydroxy groups;
  • R 1 is C 1-6 alkyl or C 3-6 cycloalkyl (C 1-6 ) alkyl, R 1 is optionally substituted with 1-4 halogens;
  • R 2 is phenyl or heteroaryl; R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, C 3-6 alkene Cycloalkyl group, -NR 4 R 5 , -SO 2 -C 1-6 alkyl and -SO 2 NR 6 R 7 ; said -R is -C 1-6 alkyl, -C 1-6 alkene Group, -C 3-6 cycloalkyl, -heterocyclyl, -aryl or -heteroaryl; said -OR is -OC 1-6 alkyl or -heterocyclyl; said -C( O)-R is -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkenyl, -C(O)-C 3-6 cycloalkyl or -C(O) -Aryl.
  • R 3 is C 1-6 alkyl or C 1-6 alkoxy (C 1-6 ) alkyl, and R 3 is optionally substituted with 1-4 hydroxy groups;
  • R 1 is C 1-6 alkyl or C 3-6 cycloalkyl (C 1-6 ) alkyl, R 1 is optionally substituted with 1-4 halogens;
  • R 2 is a phenyl group or a heteroaryl group, the heteroaryl group is a 5-6 membered monocyclic heteroaryl group or a 9-10 membered bicyclic heteroaryl group, and the 9-10 membered bicyclic heteroaryl group is 5-6 Heteroaryl groups of 5-6 membered heteroaryl groups;
  • R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, C 3-6 alkenyl cycloalkyl, -NR 4 R 5 , -SO 2 -C 1-6 alkyl and -SO 2 NR 6 R 7 ; said -R is -C 1-6 alkyl, -C 1-6 alkenyl, -C 3-6 cycloalkyl , -Heterocyclyl, -aryl or -heteroaryl; said -OR is -OC 1-6 alkyl or -heterocyclyl; said -C(O)-R is -C(O) -C 1-6 alkyl, -C(O)-C 1-6 alkenyl, -C(O)-C 3-6 cycloalkyl or -C(O)-aryl.
  • substituents independently selected from the following groups: halogen, cyan
  • R 3 is C 1-6 alkyl
  • R 1 is C 1-6 alkyl
  • R 2 is a heteroaryl group, and the heteroaryl group is a bicyclic 9-10 membered heteroaryl group consisting of a 5-6 membered heteroaryl group and a 5-6 membered heterocyclic group;
  • R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, C 3-6 alkenyl cycloalkyl, -NR 4 R 5 , -SO 2 -C 1-6 alkyl and -SO 2 NR 6 R 7 ; said -R is -C 1-6 alkyl, -C 1-6 alkenyl, -C 3-6 cycloalkyl , -Heterocyclyl, -aryl or -heteroaryl; said -OR is -OC 1-6 alkyl or -heterocyclyl; said -C(O)-R is -C(O) -C 1-6 alkyl, -C(O)-C 1-6 alkenyl, -C(O)-C 3-6 cycloalkyl or -C(O)-aryl.
  • substituents independently selected from the following groups: halogen, cyan
  • R 1 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl);
  • R 3 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl or isopropyl, and for example methyl);
  • R 2 is a heteroaryl group; the heteroaryl group is a 5-10 membered heteroaryl group, the heteroatom is N, and the number is 1, 2 or 3 (for example, a 5-6 membered monocyclic heteroaryl group or 9 A -10 membered bicyclic heteroaryl group; another example is pyridyl, pyrazolopyridyl, tetrahydronaphthyridinyl, pyrrolopyridyl, pyridazinyl or imidazopyridazinyl; another example is
  • R 2 is optionally substituted with 1-4 substituents independently selected from the following groups: cyano, -R or -OR;
  • R is independently C 1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl Group, n-propyl group, isopropyl group or tert-butyl group) or heterocyclic group (for example, a 3-10 membered heterocyclic group, the heteroatom is nitrogen and/or oxygen, the number is 1 or 2 or 3, and For example, a 5-6 membered monoheterocyclic group or a 7-8 membered heterospirocyclic group, the heteroatom is nitrogen and/or oxygen, and the number is 1 or 2, and for example, morpholinyl, pyrrolidinyl, aza Cyclobutyl, oxetanyl, piperidinyl, tetrahydropyran, tetrahydrofuran or 2-oxo-[3,3
  • R' is independently a halogen, a hydroxyl group, a 3-9 membered heterocyclic group substituted with 1-3 R'-3 (for example, a 4-6 membered monocyclic group, the heteroatom is nitrogen and/or oxygen, and a The number is 1 or 2, and for example, piperazinyl or oxetanyl, or for example ), R' -1 substituted 5-10 membered heteroaryl (for example, ) Or (C 1-6 )alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy
  • the group is, for example, methoxy, ethoxy, n-propoxy or isopropoxy, and for example, methoxy).
  • R 1 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl);
  • R 3 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl or isopropyl, and for example methyl);
  • R 2 is Y is C or N;
  • A is a 5-6 membered heterocyclic ring, the heteroatoms in the 5-6 membered heterocyclic ring are N, and the number is 1 or 2 (for example, );
  • R 2 is optionally substituted with 1-4 substituents selected from the following: C 1-6 alkyl or heterocyclic group (heterocyclic group is, for example, a 3-10 membered heterocyclic group, and the heteroatom is nitrogen and/or oxygen, The number is 1 or 2 or 3, another example is a 5-6 membered monoheterocyclic group or a 7-8 membered heterospirocyclic group, the heteroatom is nitrogen and/or oxygen, and the number is 1 or 2, another example is Is morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyran, tetrahydrofuran, or 2-oxo-[3,3]heptanyl, for example );
  • R' is independently a hydroxyl group or a 5-10 membered heteroaryl group substituted by 1-3 R'-1 (e.g., ).
  • R 1 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl);
  • R 3 is C 1-6 alkyl (for example, methyl, ethyl, n-propyl or isopropyl, and for example methyl);
  • R 2 is Y is C or N;
  • A is a 5-6 membered heterocyclic ring, the heteroatoms in the 5-6 membered heterocyclic ring are N, and the number is 1 or 2 (for example, );
  • R 2 is optionally substituted with 1-4 substituents selected from the following: C 1-6 alkyl or heterocyclic group (heterocyclic group is, for example, a 3-10 membered heterocyclic group, and the heteroatom is nitrogen and/or oxygen, The number is 1 or 2 or 3, another example is a 5-6 membered monoheterocyclic group or a 7-8 membered heterospirocyclic group, the heteroatom is nitrogen and/or oxygen, and the number is 1 or 2, another example is Is morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetrahydropyran, tetrahydrofuran, or 2-oxo-[3,3]heptanyl, for example );
  • R' is independently a hydroxyl group or a 5-10 membered heteroaryl group substituted by 1-3 R'-1 (e.g., ).
  • R 2 is optionally substituted with 1-4 C 1-6 alkyl or heterocyclic groups, the position of substitution is located on the heteroatom of ring A.
  • the compound I in its pharmaceutically acceptable salts or prodrugs, can be as follows (unannotated definitions are as described above):
  • Z is a 5-membered or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and the heteroaromatic ring may be substituted by one or more R 3;
  • R 3 is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy (C 1-6 ) alkyl, C 3-6 cycloalkyl (C 1-6 ) alkoxy, C 3-6 cycloalkyl (C 1-6 ) alkoxy (C 1-6 ) alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl (C 1-6 ) alkyl, It may each be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 alkyl and C 1-6 alkylamino;
  • R 1 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-7 heterocycloalkyl, C 3-6 cycloalkyl (C 1-6 ) alkyl, C 1-6 Alkoxy (C 1-6 )alkyl, each of which may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, hydroxy, C 1-6 alkyl, C 1 -6 alkoxy and C 1-6 alkylamino;
  • R 2 is a heterocyclic group, a phenyl group or a heteroaryl group
  • R 2 can be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C 3-6 Alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, which may each be optionally substituted by 1-3 R 'replace;
  • R' is selected from halogen, cyano, hydroxy, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6 )alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 is independently H or C 1-6 alkyl, each may be optionally substituted with 1-5 substituents, and the substituents are independently selected from: amino, halogen, hydroxy, C 1-6 Alkyl group, C 1-6 alkoxy group.
  • the compound I in its pharmaceutically acceptable salts or prodrugs, can be as follows (unannotated definitions are as described above):
  • the Z when the Z is a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, said Z contains 1, 2 or 3 independent heteroatoms.
  • the 5-membered heteroaromatic ring of heteroatoms selected from oxygen, nitrogen and sulfur is, for example, a 5-membered heteroaromatic ring containing 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, or isoxazole, for example, More for example
  • the b end is connected to the R 3 described above.
  • said R 3 is C 1-6 alkyl
  • said C 1-6 alkyl is, for example C 1-3 alkyl, or for example, methyl, ethyl, n Propyl or isopropyl is also, for example, methyl.
  • the alkyl end can be connected to the Z.
  • said R 3 is C 1-6 alkoxy C 1-6 alkyl
  • said C 1-6 alkoxy is, for example, C 1-3 alkoxy, and For example, it is methoxy, ethoxy, n-propoxy or isopropoxy, and also for example methoxy.
  • the C 1-6 alkyl is, for example, C 1-3 alkyl, or methyl Group, ethyl, n-propyl or isopropyl, also for example methyl.
  • the C 1-6 alkyl group is a C 1-3 alkyl group, for example, a methyl group or an ethyl group. , N-propyl or isopropyl, also for example methyl.
  • the number of the substituents is, for example, 1, 2, 3, 4, or 5, for example One or two.
  • the number of the substituents is, for example, 1, 2, 3, 4, or 5, or for example 1 or 2.
  • R 1 when the R 1 is C 1-6 alkyl, said C 1-6 alkyl is, for example C 1-3 alkyl, or for example, methyl, ethyl, n Propyl or isopropyl is also, for example, methyl or ethyl.
  • the R 1 is a C 3-6 cycloalkyl (C 1-6 ) alkyl group
  • the C 1-6 alkyl group is, for example, a C 1-3 alkyl group
  • Another example is methyl, ethyl, n-propyl or isopropyl, and also, for example, methyl.
  • the R 1 is a C 3-6 cycloalkyl (C 1-6 ) alkyl group
  • the C 3-6 cycloalkyl group is, for example, cyclopropyl or cyclobutyl.
  • Cyclopentyl or cyclohexyl another example is cyclopropyl or cyclobutyl.
  • the halogen is, for example, fluorine, chlorine, bromine, or iodine, or for example, fluorine.
  • the number of the substituents is, for example, 1, 2, 3, 4, or 5, for example One or two.
  • the heteroaryl group is, for example, triazolyl, pyridyl, pyridopyrrolidone, pyridopyrrolyl, pyridopyrazolyl, Pyridonyl, pyridoimidazolyl, pyridotriazolyl, pyridooxazinyl, dioxapyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridazinonyl, pyrazolopyrimidinyl, Naphthyl, naphthyridinyl, imidazopyridazinyl, naphthyridinyl, quinolinyl, such as 1,2,4-triazolyl, naphthyridinyl, for example
  • the number of the substituents is, for example, 1, 2, 3, 4, or 5, for example One or two.
  • the halogen is, for example, fluorine, chlorine, bromine or iodine, or for example, fluorine or chlorine.
  • the C 1-6 alkyl is, for example, a C 1-3 alkyl, or for example, a methyl group. And ethyl.
  • said R is C 1-6 alkyl
  • said C 1-6 alkyl is, for example C 1-3 alkyl, or for example, methyl, ethyl, n-propyl ⁇ or isopropyl.
  • the C 1-6 alkoxy is, for example, C 1-3 alkoxy, for example, methoxy, ethyl Oxy, n-propoxy or isopropoxy is also, for example, methoxy.
  • the C 1-6 alkenyl is, for example, a C 1-3 alkenyl, for example, ethylene or propylene.
  • the heterocyclic group is, for example, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, Tetrahydropyran, tetrahydrofuran, spiro ring, and for example
  • the R is a C 3-6 cycloalkyl group
  • the C 3-6 cycloalkyl group is, for example, cyclohexene, cyclopropyl, cyclobutyl, or
  • the heteroaryl is, for example, pyrimidinyl, oxadiazole, or
  • the number of the substituents is, for example, 1, 2, 3, 4, or 5, or for example 1 or 2 or 3.
  • the R' is C 1-6 alkoxy
  • the C 1-6 alkoxy is, for example, C 1-3 alkoxy, or methoxy
  • Ethoxy, n-propoxy or isopropoxy is also, for example, methoxy.
  • said R' is C 1-6 alkylamino
  • said C 1-6 alkylamino is, for example, C 1-3 alkylamino, or for example, ethylamino
  • NHEt is NHEt.
  • the halogen is, for example, fluorine, chlorine, bromine, or iodine, or for example, fluorine.
  • the C 3-6 cycloalkyl group is, for example, a cyclopropyl group.
  • the heteroaryl is, for example, pyrimidinyl, or
  • the heterocyclic group is, for example, tetrahydrofuran, oxetanyl, azetidinyl, morpholinyl, piperazinyl, and
  • the heterocyclic group is, for example, tetrahydrofuran, oxetanyl, azetidinyl, morpholinyl, piperazinyl, and
  • the C 1-6 alkyl sulfone is, for example, -SO 2 Me, -CH 2 CH 2 SO 2 Me, and For example, -SO 2 Me.
  • said R 4 or R 5 is C 1-6 alkyl
  • said C 1-6 alkyl is, for example C 1-3 alkyl, and for example, methyl, ethyl Group, n-propyl or isopropyl, also for example methyl, ethyl or n-propyl.
  • the halogen is, for example, fluorine, chlorine, bromine, or iodine, or for example, fluorine.
  • the substituents are, for example, halogen, for example fluorine, chlorine, bromine or iodine, or for example fluorine.
  • the number of the substituents is, for example, 1, 2, 3, or 4. Or 5, for example, 1 or 2 or 3.
  • X is N or CH
  • R 1 is selected from C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and C 3-6 cycloalkyl substituted C 1-6 alkyl;
  • R 3 is selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, and C 1-6 alkoxy substituted C 1-6 alkyl.
  • R 2 is phenyl or heteroaryl
  • R 2 substituents may optionally be independently 1 to 4 substituents selected from the group: halo, cyano, oxo, -R, -OR, -C (O ) R, -NHR, C 3- 6 alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, which may each be optionally substituted by 1-3 R 'replace.
  • R' is selected from halogen, cyano, hydroxy, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6 )alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 is independently H or C 1-6 alkyl, C 1-6 alkyl may be substituted by 1-5 substituents, and the substituents are independently selected from: amino, halogen, halogenated C 1 -6 alkoxy, hydroxyl, C 1-6 alkoxy.
  • X is N or CH
  • R 1 is selected from C 1-3 alkyl, fluorine substituted C 1-3 alkyl, or C 3-6 cycloalkyl substituted C 1-3 alkyl;
  • R 3 is selected from C 1-3 alkyl, hydroxy substituted C 1-3 alkyl, or C 1-3 alkoxy substituted C 1-3 alkyl.
  • R 2 is phenyl or heteroaryl
  • R 2 substituents may optionally be independently 1 to 4 substituents selected from the group: halo, cyano, oxo, -R, -OR, -C (O ) R, -NHR, C 3- 6 alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, which may each be optionally substituted by 1-3 R 'replace.
  • R' is selected from halogen, cyano, hydroxy, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6 )alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 is independently H or C 1-6 alkyl, C 1-6 alkyl may be substituted by 1-5 substituents, and the substituents are independently selected from: amino, halogen, halogenated C 1 -6 alkoxy, hydroxyl, C 1-6 alkoxy.
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, methoxymethyl
  • R 2 is phenyl or heteroaryl
  • R 2 may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 Alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from H, C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, which may each be optionally substituted by 1-3 R 'replace.
  • R' is selected from halogen, cyano, hydroxy, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6) alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 is independently H or C 1-6 alkyl, C 1-6 alkyl may be substituted by 1-5 substituents, and the substituents are independently selected from: amino, halogen, halogenated C 1 -6 alkoxy, hydroxyl, C 1-6 alkoxy.
  • X is N or CH
  • R 1 is selected from C 1-6 alkyl, halogen-substituted C 1-6 alkyl, and C 3-6 cycloalkyl substituted C 1-6 alkyl;
  • R 3 is selected from C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy substituted C 1-6 alkyl;
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridonyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 substituents may optionally be independently 1 to 4 substituents selected from the group: halo, cyano, oxo, -R, -OR, -C (O ) R, -NHR, C 3- 6 alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, each of which may be optionally substituted by 1-3 R' ;
  • R' is selected from halogen, cyano, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6 )alkoxy, cyano or halogen substituted C 1 --3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 are independently selected from H, C 1-6 alkyl substituted with 1-5 halogens.
  • X is N or CH
  • R 1 is selected from C 1-3 alkyl, fluorine substituted C 1-3 alkyl, or C 3-6 cycloalkyl substituted C 1-3 alkyl;
  • R 3 is selected from C 1-3 alkyl, hydroxy substituted C 1-3 alkyl, or C 1-3 alkoxy substituted C 1-3 alkyl.
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridonyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 Alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, each of which may be optionally substituted by 1-3 R' ;
  • R' is selected from halogen, cyano, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6 )alkoxy, cyano or halogen substituted C 1 --3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 are independently selected from H, C 1-6 alkyl substituted with 1-5 halogens.
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridonyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 may be optionally substituted with 1-4 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, C3-6 Alkenyl cycloalkyl, -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-6 alkyl;
  • R is selected from C 1-6 alkyl, C 1-6 alkenyl, C 3-6 cycloalkyl, heterocyclyl, aryl, heteroaryl, each of which may be optionally substituted by 1-3 R' ;
  • R' is selected from halogen, cyano, C 3-6 cycloalkyl, C 1-6 alkylamino, C 1-6 alkyl, (C 1-6) alkoxy, cyano or halogen substituted C 1 --3 alkyl, C 1-6 alkyl sulfone, heterocyclyl, heteroaryl;
  • R 4 or R 5 are independently selected from H, C 1-6 alkyl substituted with 1-5 halogens.
  • X is N or CH
  • R 1 is selected from C 1-3 alkyl, fluorine substituted C 1-3 alkyl, or C 3-6 cycloalkyl substituted C 1-3 alkyl;
  • R 3 is selected from C 1-3 alkyl, hydroxy substituted C 1-3 alkyl, or C 1-3 alkoxy substituted C 1-3 alkyl;
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridonyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 can be optionally substituted with 1-2 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, cyclohexene , -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-3 alkyl;
  • R is selected from C 1-3 alkyl, C 1-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetra Hydropyran, tetrahydrofuran, spiro ring, aryl, pyrimidinyl, oxadiazole, each of which may be optionally substituted with 1 to 3 R';
  • R' is selected from halogen, cyano, cyclopropyl, C 1-3 alkylamino, C 1-3 alkyl, C 1-3 alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-3 alkyl sulfone, tetrahydrofuran, oxetanyl, azetidinyl, morpholinyl, piperazinyl, methylpiperazine, pyrimidinyl;
  • R 4 or R 5 is selected from H, C 1-3 alkyl substituted with 1-3 fluorines.
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 can be optionally substituted with 1-2 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, cyclohexene , -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-3 alkyl;
  • R is selected from C 1-3 alkyl, C 1-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetra Hydropyran, tetrahydrofuran, spiro ring, aryl, pyrimidinyl, oxadiazole, each of which may be optionally substituted with 1 to 3 R';
  • R' is selected from halogen, cyano, cyclopropyl, C 1-3 alkylamino, C 1-3 alkyl, C 1-3 alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-3 alkyl sulfone, tetrahydrofuran, oxetanyl, azetidinyl, morpholinyl, piperazinyl, methylpiperazine, pyrimidinyl;
  • R 4 or R 5 is selected from H, C 1-3 alkyl substituted with 1-3 fluorines.
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • R 2 is selected from phenyl and the following substituents:
  • R 2 can be optionally substituted with 1-2 substituents independently selected from the following groups: halogen, cyano, oxo, -R, -OR, -C(O)R, -NHR, cyclohexene , -NR 4 R 5 , -C(O)NR 4 R 5 , -COOH, -SO 2 -C 1-3 alkyl;
  • R is selected from C 1-3 alkyl, C 1-3 alkenyl, cyclopropyl, cyclobutyl, morpholinyl, pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, tetra Hydropyran, tetrahydrofuran, spiro ring, aryl, pyrimidinyl, oxadiazole, each of which may be optionally substituted with 1 to 3 R';
  • R' is selected from halogen, cyano, cyclopropyl, C 1-3 alkylamino, C 1-3 alkyl, C 1-3 alkoxy, cyano or halogen substituted C 1-3 alkyl, C 1-3 alkyl sulfone, tetrahydrofuran, oxetanyl, azetidinyl, morpholinyl, piperazinyl, methylpiperazine, pyrimidinyl;
  • R 4 or R 5 is selected from H, C 1-3 alkyl substituted with 1-3 fluorines.
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, and methoxymethyl.
  • R 2 is selected from phenyl, triazolyl, pyridyl, triazolopyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrazinyl, pyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl , Dihydropyrrolopyridinyl, dihydropyrrolidopyridinyl, pyrazolopyridinyl, imidazopyridinyl, imidazopyridazinyl, pyridooxazinyl, 1,4-dioxapyridinyl, imidazole Pyridazinyl, heteronaphthyl, naphthyridinyl, naphthyridinyl, dihydronaphthyridinyl, quinolinyl;
  • R 2 can be optionally substituted with 1-4 substituents independently selected from the following groups: -Me, -Et, -iPr, -CF 3 , -OCF 3 , -OCHF 2 , -Cl, -F, -CN, -OMe, -OEt, -NMe 2 , -CH 2 CF 3 , -(CH2)2CN, -(CH 2 ) 3 CN, -CH 2 NHEt, -OCHF 2 , -OCH(CH 3 ) 2 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 3 OCH 3 , -SO 2 Me, -CH 2 CH 2 SO 2 Me, -COOH,
  • X is N or CH
  • R 1 is selected from methyl, ethyl, cyclopropylmethyl, difluoromethyl
  • R 3 is selected from methyl, hydroxymethyl, methoxymethyl
  • R 2 is selected from phenyl and the following substituents:
  • R 2 can be optionally substituted with 1-4 substituents independently selected from the following groups: -Me, -Et, -i Pr, -CF 3 , -OCF 3 , -OCHF 2 , -Cl, -F , -CN, -OMe, -OEt, -NMe 2 , -CH 2 CF 3 , -(CH 2 ) 2 CN, -(CH 2 ) 3 CN, -CH 2 NHEt, -OCHF 2 , -OCH(CH 3 ) 2 , -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 3 OCH 3 , -SO 2 Me, -CH 2 CH 2 SO 2 Me, -COOH,
  • the compound I is any one of the following compounds:
  • the present invention also provides a method for producing the above-mentioned compound represented by formula I or II, the method comprising:
  • compound 1 is provided by commercial raw materials.
  • compound 1 with special structure it can be obtained by substitution reaction of corresponding alcohol with compound 8 in step a, generally in alkaline reagents, such as sodium metal, sodium hydride, tert-butanol In the presence of potassium, etc., react in ethers or corresponding alcohol solvents;
  • the preparation of compound 3 can be prepared by heating the corresponding hydrazide and compound 1 in various ether or alcohol solvents under acid catalysis, such as p-toluenesulfonic acid, in step c. Different regioisomers are produced and need to be separated; or, for the less reactive substrate, the hydrazide can be reacted with compound 1 under similar conditions to c through step b, and then compound 2 can be separated, and further through step d in alcohol Class, acetic acid and other solvents are heated to close the ring, and the isomers are separated to obtain compound 3.
  • acid catalysis such as p-toluenesulfonic acid
  • Compound 7 can be obtained from the corresponding ester compound 6 by, for example, sodium borohydride, lithium aluminum hydride in ethers, alcohols and other solvents through step i reduction; in addition, for the complex structure of the ester compound 6 can be obtained from The corresponding halogenated heteroaryl ester, or heteroaryl ester substituted by phenolic hydroxyl group is obtained through step h, substitution, coupling and other reactions;
  • Compound (I) can be directly generated by the substitution reaction of compound 3 and compound 7 in step f, corresponding to basic conditions, such as cesium carbonate, potassium phosphate, etc., reacting in various solvents such as DMF, acetonitrile, etc.; or, it can be produced by Compound 3 is converted into the corresponding phenolic compound 4 under alkaline conditions, such as sodium hydroxide, potassium hydroxide, etc., in step e, and then with the corresponding commercially available halogenated compound under alkaline conditions such as carbonic acid in step g Silver, cesium carbonate, etc. can be obtained by substituting it.
  • basic conditions such as cesium carbonate, potassium phosphate, etc.
  • the present invention also relates to the compound of general formula (I) or (II) as described above, which is prepared by the method as described above.
  • the compound of general formula (I) or (II) and its intermediate products can be prepared according to a similar method or according to the aforementioned method.
  • Raw materials known in the art can be obtained commercially, or can be prepared according to methods known in the art or similar methods to known methods.
  • the compound of the general formula (I) or (II) of the present invention can be derivatized on a functional group, thereby obtaining a derivative that can be converted into the parent compound in vivo.
  • the compound of general formula (I) or (II) and its intermediate products can be prepared according to a similar method or according to the aforementioned method.
  • Raw materials known in the art can be obtained commercially, or can be prepared according to methods known in the art or similar methods to known methods.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound represented by formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, Its solvates, its hydrates, or pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable excipients.
  • the present invention also provides a compound of formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, The use of its hydrate or its pharmaceutically acceptable salt or its prodrug or the above-mentioned pharmaceutical composition in the preparation of medicine.
  • the drug can be used to treat, prevent or ameliorate diseases related to ⁇ 5-GABA A receptors.
  • the diseases related to ⁇ 5-GABA A receptors are, for example, cognitive diseases, Alzheimer's disease, memory impairment, Down's syndrome, amyotrophic lateral sclerosis (ALS), drug addiction, lower limb failure
  • ALS amyotrophic lateral sclerosis
  • the drug can be used to treat, prevent or ameliorate the following diseases: cognitive diseases, Alzheimer's disease, memory impairment, Down syndrome, amyotrophic lateral sclerosis (ALS), drugs One or more of addiction, restless lower limb syndrome, cognitive deficit, multi-infarct dementia, pain, stroke, and attention deficit, for example, pain.
  • cognitive diseases Alzheimer's disease, memory impairment, Down syndrome, amyotrophic lateral sclerosis (ALS), drugs
  • ALS amyotrophic lateral sclerosis
  • drugs One or more of addiction, restless lower limb syndrome, cognitive deficit, multi-infarct dementia, pain, stroke, and attention deficit, for example, pain.
  • the pain is one or more of neuropathic pain, inflammatory pain and cancer pain.
  • the pain is selected from: headache, facial pain, neck pain, shoulder pain, back pain, chest pain, abdominal pain, back pain, low back pain, lower limb pain, muscle and bone pain, vascular pain, gout , Arthritis pain, visceral pain, pain caused by infectious diseases (such as AIDS and post-herpetic neuralgia), bony pain, sickle cell anemia, autoimmune disease, multiple sclerosis or inflammation-related pain, injury or Chronic pain caused by surgery, nociceptive pain, painful diabetes, trigeminal neuralgia, lumbar or cervical radiculopathy, glossopharyngeal neuralgia, autonomic reflex pain, reflex sympathetic dystrophy, nerve root avulsion, cancer , Chemical damage, toxins, nutritional deficiencies, viral or bacterial infections, and pain related to degenerative osteoarthropathy.
  • infectious diseases such as AIDS and post-herpetic neuralgia
  • bony pain bony pain
  • autoimmune disease multiple sclerosis or inflammation-related pain
  • injury or Chronic pain caused by surgery nocic
  • the present invention also provides a compound of formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, The use of its hydrate or its pharmaceutically acceptable salt or its prodrug, or the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment or prevention of diseases related to ⁇ 5-GABA A receptors.
  • diseases related to ⁇ 5-GABA A receptors are as described in the present invention.
  • the present invention also provides a compound of formula I, its cis-trans isomer, its enantiomer, its diastereomer, its racemate, its solvate, Its hydrate or its pharmaceutically acceptable salt or its prodrug, or the use of the pharmaceutical composition in the preparation of a medicine for the treatment or prevention of diseases, the diseases being pain, Alzheimer's disease, One or more of multi-infarct dementia and stroke. Wherein, the pain is as described in the present invention.
  • the present invention also provides a method for treating or preventing diseases related to ⁇ 5-GABA A receptors, comprising administering to a patient an effective dose of the above-mentioned compound represented by formula I, its cis-trans isomer, and its enantiomer Conformer, its diastereomer, its racemate, its solvate, its hydrate or its pharmaceutically acceptable salt or its prodrug, or the above-mentioned pharmaceutical composition.
  • the above-mentioned compound represented by formula I may be an effective dose.
  • the above-mentioned compound represented by formula I in the composition, use and method of the present invention, can be used in combination with other drugs.
  • the present invention also provides the use of the compounds or compositions described herein in the preparation of medicines for the treatment or prevention of the following diseases: pain, Alzheimer's disease, multi-infarct dementia and stroke.
  • the present invention also provides a method for treating or preventing diseases, comprising administering to a patient an effective dose of the above-mentioned compound represented by formula I, its cis-trans isomers, its enantiomers, and its diastereomers Body, its racemate, its solvate, its hydrate or its pharmaceutically acceptable salt or its prodrug, or the above-mentioned pharmaceutical composition, said disease is pain, Alzheimer’s disease, One or more of multi-infarct dementia and stroke. Wherein, the pain is the same as that described in the present invention.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included in the scope of the present invention.
  • substituted means that the specified group or moiety may have 1, 2, 3, 4, 5, or 6 substituents.
  • substituents are independently selected and do not have to be the same.
  • substituents When specifying the number of substituents, the term "one or more" refers to the maximum possible number of substitutions from one substitution to substitution, that is, one hydrogen is substituted to all hydrogens are substituted by substituents. Unless otherwise specified, 1, 2, 3, 4 or 5 substituents are preferred.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • cycloalkyl refers to a monovalent saturated cyclic hydrocarbon group including bridged rings and spiro rings, preferably having 3-7 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the following Those groups specifically exemplified in the text.
  • heterocycle or “heterocyclyl” means that 1 to 4 carbon atoms have been replaced by heteroatoms independently selected from N, N(R), S, S(O), S(O) and O Cyclic hydrocarbon. Heterocycles can be saturated or unsaturated, but are not aromatic. The heterocyclic group can also contain 1, 2 or 3 rings, including bridged rings and spiro ring structures.
  • heterocyclic groups include, but are not limited to: azetidine, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolane Group, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolanyl, oxathiolanyl, dioxanyl , Dioxenyl, dioxazolyl, oxathiozolyl, oxazolyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithiazolyl, Trithiaalkyl and oxazinyl.
  • bridged ring compound refers to one or more atoms (ie, C, O, N, or S) connecting two non-adjacent carbon atoms or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring to a three ring. In bridged rings, substituents on the ring may also appear on the bridge.
  • spiro compound refers to a polycyclic compound in which two monocyclic rings share one carbon atom.
  • the shared carbon atom is called a spiro atom.
  • aryl refers to a monovalent aromatic carbocyclic ring system containing 6-14, preferably 6-10 carbon atoms and having at least one aromatic ring or multiple condensed rings in which at least one ring is an aromatic ring.
  • aryl groups are phenyl, naphthyl, biphenyl or indanyl, and those specifically exemplified below.
  • the preferred aryl group is phenyl, which can also be substituted, as defined below and in the claims.
  • heteroaryl means a stable monocyclic, bicyclic, or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 selected from O, N and S heteroatom.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H , 3H-1-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl, benzothienyl, benzofuran Group, benzodioxane, benzodioxabenzene, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, Pyridyl, pyrimidinyl, pyrrolyl, te
  • heteroaryl groups have 5- or 6-membered rings, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrole Group, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridomorpholinyl, pyridopiperidinyl, pyridopyrrolidinyl.
  • Heteroaryl groups may also be substituted, as defined below and in the claims.
  • the compounds of general formula (I) or (II) can form pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable salts are salts formed by compounds of general formula (I) or (II) and physiologically compatible inorganic or organic acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid;
  • the organic acid is, for example, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • pharmaceutically acceptable salts refers to such salts.
  • the compound of formula (I) or (II) containing an acidic group such as COOH may also form a salt with a base.
  • salts are alkali metal, alkaline earth metal and ammonium salts, such as Na-, K-, Ca- and trimethylammonium salts.
  • pharmaceutically acceptable salts also refers to such salts.
  • prodrug generally refers to the functional group derivatization of a compound of general formula (I) or (II), and its derivative can be easily converted into a compound of general formula (I) or (II) in vivo.
  • suitable prodrug selection and preparation can be referred to, for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • the isotopes have the same atomic number, but their atomic mass or mass number is different from those that predominantly exist in nature. Atomic mass or mass number.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • Isotopic variants may increase certain therapeutic advantages, such as deuterium enrichment can increase in vivo half-life or reduce dosage requirements, or can provide standard compounds that can be used as the characterization of biological samples. It can be prepared by conventional techniques well-known to those skilled in the art, or by methods similar to those described in the routes and examples herein, using appropriate isotope-enriched reagents and/or intermediates, without undue experimentation. Isotopically enriched compounds within the general formula I.
  • the new compound of the present invention and its pharmaceutically acceptable salts and prodrugs have important pharmacological properties and are ⁇ 5GABA A receptor inverse agonists. Therefore, the compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of diseases mediated by GABA A receptor ligands containing ⁇ 5 subunits. These diseases include but are not limited to pain, Alzheimer's disease, multi-infarct dementia, and stroke.
  • the present invention also relates to a pharmaceutical composition, which comprises a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
  • the present invention also includes the compounds as described above for use in the preparation of drugs for the treatment or prevention of diseases related to ⁇ 5GABA A receptors, especially for the treatment or prevention of the following diseases: pain, Alzheimer's disease, and multi-infarct dementia And stroke.
  • cancer pain refers to the pain that occurs during the development of malignant tumors.
  • cancer pain There are currently three mechanisms for cancer pain, namely: pain directly caused by cancer development, pain caused by cancer chemotherapy drugs, and Cancer patients are complicated by painful diseases.
  • neurode pain refers to pain triggered or caused by primary damage and dysfunction of the nervous system.
  • inflammatory pain refers to pain caused by local acute inflammation or chronic inflammation that stimulates nerves.
  • treatment also includes prophylactic administration to alleviate or eliminate the condition once the condition is established.
  • patient is defined as any warm-blooded animal, such as but not limited to mice, guinea pigs, dogs, horses, or humans, and the patient is preferably human.
  • acute pain is defined as pain caused by damage to the skin, body structure, or internal organs and/or harmful irritation from disease, or pain caused by abnormal function of muscles or internal organs that do not produce actual tissue damage .
  • chronic pain is defined as a duration beyond the usual course of an acute disease or a reasonable time for the injury to heal, or is related to a chronic pathological process that causes persistent pain, or pain recurs at regular intervals for months or years, if it should be Pain is considered to be chronic pain after healing or beyond the usual course of treatment.
  • the length of time that the pain needs to elapse depends on the nature of the pain and the treatment process related to the pain. If the pain exceeds the usual treatment process, the pain is chronic.
  • the drug disclosed in the present invention can effectively treat chronic pain as defined above, and the drug disclosed in the present invention can be used to treat hyperalgesia associated with other diseases, including hyperalgesia, allodynia, increased pain sensation, and enhanced pain memory.
  • the invention will improve Treatment of its pain.
  • headache can be divided into primary headaches and secondary headaches.
  • Primary headaches include tension headaches, migraines, and cluster headaches, while secondary headaches are caused by other diseases.
  • pain-sensitive tissues of the head and face are diseased or stimulated, it can cause various headaches.
  • These pain-sensitive tissues include the scalp, face, mouth and throat, etc., because they are mainly the muscles or blood vessels of the head, and they are rich in nerves. Fiber is more sensitive to pain, so when these tissues are injured, it can cause headaches.
  • facial pain includes, but is not limited to, trigeminal neuralgia, atypical facial pain, facial nerve palsy, and hemifacial spasm.
  • trigeminal neuralgia is a unique chronic painful disease, also known as painful convulsions. It refers to transient, paroxysmal and repeated shock-like severe pain in the trigeminal nerve distribution area. Or accompanied by ipsilateral muscle spasm. Trigeminal neuralgia is divided into two types, primary and secondary. Primary trigeminal neuralgia refers to clinically no signs of the nervous system and no organic disease found on examination; secondary trigeminal neuralgia refers to clinical There are signs of the nervous system, and the examination reveals organic diseases such as tumors and inflammation.
  • typical facial pain refers to pain caused by multiple causes. It is characterized by continuous burning pain, non-intermittent, and has nothing to do with special movements or triggering stimuli. The pain is mostly bilateral, and the pain often exceeds the distribution of the trigeminal nerve and even involves the skin of the neck.
  • the cause of the disease can be sinusitis, malignant tumors, jaw and skull base infections and other reasons to stimulate or damage the trigeminal nerve and cause pain.
  • neck pain, back pain, shoulder pain refers to pain caused by acute and chronic muscle strain, degeneration of bones and joints, and trauma.
  • Common diseases that cause neck, shoulder and upper limb pain include cervical shoulder myofasciitis, nape ligamentitis, cervical spondylosis, frozen shoulder, thoracic outlet syndrome, external humeral epicondylitis, etc., or pain caused by autoimmune diseases It is common in diseases such as rheumatoid arthritis, ankylosing spondylitis and rheumatoid arthritis.
  • Other diseases that may cause neck pain, back pain and shoulder pain include neck and shoulder tumors, neuritis, arteriovenous diseases and various diseases. Involvement pain caused by various infections and chest and abdominal organ diseases.
  • chest, abdomen, and back pain refers to pain caused by diseases of the internal organs of the chest and abdomen, the chest and abdomen wall tissues.
  • lumbar and lower limb pain refers to lower back, lumbosacral, sacroiliac, hip, buttock, and lower limb pain.
  • muscle and bone pain includes, but is not limited to, myofascial pain, trauma-induced pain, and chronic regional pain syndrome.
  • diabetes peripheral neuropathic pain refers to the pain caused by nerve damage complicated by diabetes.
  • the nerve damage in diabetes is at least partly caused by reduced blood flow and hyperglycemia.
  • visceral pain includes, but is not limited to, irritable bowel syndrome (IBS), pain with or without chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), and interstitial cystitis .
  • IBS irritable bowel syndrome
  • CFS chronic fatigue syndrome
  • IBD inflammatory bowel disease
  • interstitial cystitis interstitial cystitis
  • vascular pain is pain caused by one or more of the following factors.
  • First, improper tissue perfusion. Cause temporary or continuous ischemia, such as ischemia in limb muscles during exercise; second, delayed changes. For example, ulcers or gangrene in the skin or abdominal internal organs; third, sudden or accelerated changes in the diameter of large blood vessels. For example, changes in aneurysms; fourth, aortic rupture.
  • autonomic reflex pain refers to pain caused by "reflex sympathetic atrophy”.
  • Reflex sympathetic atrophy refers to severe spontaneous pain after the body suffers acute or chronic injury, hypersensitivity to touch and hyperalgesia.
  • postoperative pain refers to a complex physiological response of the body to the disease itself and tissue damage caused by surgery, which manifests as an unpleasant psychological and behavioral experience.
  • arthritis pain includes, but is not limited to, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthropathy, gout, pseudogout, infectious arthritis, tendinitis, mucus sac Pain caused by diseases such as inflammation, bone damage and joint soft tissue inflammation.
  • neuralgia after shingles refers to severe pain that exists under the skin of the original rash area for a long time after the rash of shingles has healed.
  • nociceptive pain is the pain caused by the tissue damage process that stimulates the incoming nociceptors, or the pain caused by the prolonged excitement of the nociceptors.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that the triazolopyridazine derivatives of the present invention have good inverse agonistic activity, thermodynamic solubility, bioavailability and pharmacokinetic properties for ⁇ 5-GABA A.
  • a mixture of oxazine and the isomer 6-chloro-4-methoxy-3-(pyridine-2-methoxy)pyridazine (11 g, 52%), proceed to the next step without further purification.
  • LC-MS: m/z[M+H] + 433.
  • magnesium powder (1.154 g, 48 mmol) was added to a three-necked flask, and THF (2 mL) was added. Under the condition of 40°C, the initiator isopropylmagnesium chloride lithium chloride complex solution (dissolved in tetrahydrofuran, 1.3M, 0.96mL, 0.74mmol) was added. The raw material bromocyclobutane (5.0 g, 37 mmol) was dissolved in tetrahydrofuran (30 mL) and gradually added to the reaction solution. React at 40°C for 2 hours.
  • trimethylsilyl diazomethane (4.68 mL, 9.36 mmol, 2M n-hexane solution) were added to dichloromethane (4 mL) and methanol (0.5 mL) successively, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with dichloromethane, dried, and concentrated to obtain 260 mg of the crude title compound. This and sodium borohydride (206 mg, 5.4 mmol) were added to tetrahydrofuran (6 mL) and methanol (1.5 mL) in turn. The reaction mixture was stirred at room temperature for 16 hour.
  • the lutidine-2,5-dicarboxylate (4g, 20mmol) was dissolved in 200mL of dichloromethane, cooled to 0°C, and m-chloroperoxybenzoic acid (10.6g, 61mmol) was added in batches.
  • the reaction solution was poured into an aqueous sodium thiosulfate solution, and sodium sulfate was extracted with dichloromethane to dry and concentrate.
  • reaction solution was poured into 20 mL of sodium bicarbonate aqueous solution for quenching, extracted with dichloromethane, dried and concentrated to obtain 3-(6-(acetoxymethyl)pyridin-3-yl)-2,5-bis 300 mg of tert-butyl hydrogen-1H-pyrrole-1-carboxylate was dissolved in 5 mL of tetrahydrofuran, lithium hydroxide monohydrate (60 mg, 1.4 mmol) was added, and the mixture was stirred at room temperature for 3 hours.

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Abstract

L'invention concerne un dérivé de triazolopyridazine, son procédé de préparation, une composition pharmaceutique associée et une utilisation correspondante. Le dérivé de triazolopyridazine est représenté par la formule I. Le dérivé de triazolopyridazine a une excellente activité agoniste inverse, une solubilité thermodynamique, une biodisponibilité et d'excellentes propriétés pharmacocinétiques ; ainsi il présente des perspectives d'application prometteuses.
PCT/CN2020/136998 2019-12-16 2020-12-16 Dérivé de triazolopyridazine, son procédé de préparation, composition pharmaceutique associée et utilisation correspondante WO2021121294A1 (fr)

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US17/786,528 US20230136194A1 (en) 2019-12-16 2020-12-16 Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof
PE2022001105A PE20221517A1 (es) 2019-12-16 2020-12-16 Derivado de triazolopiridazina, metodo de preparacion del mismo, composicion farmaceutica del mismo y uso del mismo
AU2020410470A AU2020410470B2 (en) 2019-12-16 2020-12-16 Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof
CN202080061283.4A CN114302886B (zh) 2019-12-16 2020-12-16 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途
JP2022537266A JP7417742B2 (ja) 2019-12-16 2020-12-16 トリアゾロピリダジン系誘導体、その調製方法、医薬組成物及び使用
BR112022011946A BR112022011946A2 (pt) 2019-12-16 2020-12-16 Derivado de triazolopiridazina, método de preparação para o mesmo, composição farmacêutica do mesmo, e uso do mesmo
IL293959A IL293959A (en) 2019-12-16 2020-12-16 A triazolopyridazine derivative, a method for its preparation, a pharmaceutical preparation thereof and its use
EP20904065.8A EP4079734A4 (fr) 2019-12-16 2020-12-16 Dérivé de triazolopyridazine, son procédé de préparation, composition pharmaceutique associée et utilisation correspondante
MX2022007426A MX2022007426A (es) 2019-12-16 2020-12-16 Derivado de triazolopiridazina, metodo de preparacion del mismo, composicion farmaceutica del mismo y uso del mismo.
CA3161739A CA3161739A1 (fr) 2019-12-16 2020-12-16 Derive de triazolopyridazine, son procede de preparation, composition pharmaceutique associee et utilisation correspondante
KR1020227024733A KR20220140710A (ko) 2019-12-16 2020-12-16 트리아졸로피리다진 유도체, 이의 제조 방법, 약물 조성물 및 용도
CONC2022/0009489A CO2022009489A2 (es) 2019-12-16 2022-07-06 Derivado de triazolopiridazina, método de preparación del mismo, composición farmacéutica del mismo y uso del mismo

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CN114591352A (zh) * 2022-05-11 2022-06-07 上海赛默罗生物科技有限公司 一种三唑并哒嗪类化合物及其应用
CN114591352B (zh) * 2022-05-11 2022-09-09 上海赛默罗生物科技有限公司 一种三唑并哒嗪类化合物及其应用
CN114773352A (zh) * 2022-06-20 2022-07-22 上海赛默罗生物科技有限公司 制备取代的烟酰胺的方法

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